Boxed warning

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An exemplary black box warning, as seen in context, in FDA's Challenges and Issues with Safety-Related Information in the Prescribing Information slide desk. For emphasis, the text is bolded and surrounded by a black outline. Boxed warning in context FDA example.jpg
An exemplary black box warning, as seen in context, in FDA's Challenges and Issues with Safety-Related Information in the Prescribing Information slide desk. For emphasis, the text is bolded and surrounded by a black outline.

In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it is formatted with a 'box' or border around the text [1] to emphasize it is of utmost importance. [2] The FDA can require a pharmaceutical company to place a boxed warning. It is the strongest warning that the FDA requires, and signifies that medical studies indicate that the drug carries a significant risk of preventable, serious or even life-threatening adverse effects. [2] [3]

Contents

Economists and physicians have thoroughly studied the effects of FDA boxed warnings on prescription patterns. It is not necessarily true that a physician and patient will have a conversation about a drug's boxed warning after it is issued. [4] For instance, an FDA-mandated boxed warning decreased rosiglitazone use by 70%, but that still meant 3.8 million people were given the drug. Later research indicated that after receiving an FDA advisory, there was a decrease in rosiglitazone use, due to a combined effect of media exposure, advisory, and scientific publications, whereas pioglitazone (with a similar advisory but less media exposure) did not similarly decrease in use. [5]

Examples

Boxed warnings on drugs have received increased media attention in the United States since 2004. Among some of the more widely covered stories:

In other jurisdictions

In China, a warning text (警示语) may be added to a package insert, either voluntarily by the manufacturer or at the request of NMPA (formerly CFDA, the Chinese counterpart of FDA). Although no formatting requirement is found in law, the typical formatting is similar to the American counterpart with black-boxed text at the top of the insert. The CFDA/NMPA has used its power to mandate a warning on fluoroquinolones, ceftriaxone, aciclovir, and pioglitazone. [25]

Health Canada terms its version of boxed warnings "serious warnings and precautions box". [26] The formatting is similar to the US counterpart; an example for Paxlovid can be seen on Pfizer's website. [27]

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<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.

<span class="mw-page-title-main">Ziprasidone</span> Antipsychotic medication

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation in people with schizophrenia.

<span class="mw-page-title-main">Aripiprazole</span> Atypical antipsychotic

Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder; other uses include as an add-on treatment in major depressive disorder and obsessive compulsive disorder (OCD), tic disorders, and irritability associated with autism. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

<span class="mw-page-title-main">Loxapine</span> Antipsychotic medication

Loxapine, sold under the brand names Loxitane and Adasuve among others, is a tricyclic antipsychotic medication used primarily in the treatment of schizophrenia. The medicine is a member of the dibenzoxazepine class and structurally very similar to clozapine. Several researchers have argued that loxapine, initially classified as a typical antipsychotic, behaves as an atypical antipsychotic.

<span class="mw-page-title-main">Naproxen</span> Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours.

<span class="mw-page-title-main">Rosiglitazone</span> Chemical compound

Rosiglitazone is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis in 2007 that linked the drug's use to an increased risk of heart attack, sales plummeted to just $9.5-million in 2012. The drug's patent expired in 2012.

<span class="mw-page-title-main">Celecoxib</span> Nonsteroidal anti-inflammatory medication

Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.

Cyclooxygenase-2 inhibitors, also known as coxibs, are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly target cyclooxygenase-2 (COX-2), an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of celecoxib, rofecoxib, and other members of this drug class.

<span class="mw-page-title-main">Dextropropoxyphene</span> Withdrawn opioid medication

Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive and local anaesthetic effects. The drug has been taken off the market in Europe and the US due to concerns of fatal overdoses and heart arrhythmias. It is still available in Australia, albeit with restrictions after an application by its manufacturer to review its proposed banning. Its onset of analgesia is said to be 20–30 minutes and peak effects are seen about 1.5–2.0 hours after oral administration.

<span class="mw-page-title-main">Sibutramine</span> Appetite suppressant

Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor similar to a tricyclic antidepressant. Until 2010, it was widely marketed and prescribed as an adjunct in the treatment of obesity along with diet and exercise. It has been associated with increased cardiovascular diseases and strokes and has been withdrawn from the market in 2010 in several countries and regions including Australia, Canada, China, the European Union, Hong Kong, India, Mexico, New Zealand, the Philippines, Thailand, the United Kingdom, and the United States. However, the drug remains available in some countries.

<span class="mw-page-title-main">Prochlorperazine</span> Medication for nausea, psychosis, and anxiety

Prochlorperazine, formerly sold under the brand name Compazine among others, is a medication used to treat nausea, migraines, schizophrenia, psychosis and anxiety. It is a less preferred medication for anxiety. It may be taken by mouth, rectally, injection into a vein, or injection into a muscle.

<span class="mw-page-title-main">Meloxicam</span> Nonsteroidal anti-inflammatory drug (NSAID)

Meloxicam, sold under the brand name Mobic among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation in rheumatic diseases and osteoarthritis. It is used by mouth or by injection into a vein. It is recommended that it be used for as short a period as possible and at a low dose.

<span class="mw-page-title-main">Natalizumab</span> Medication used to treat multiple sclerosis and Crohns disease

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.

<span class="mw-page-title-main">Dronedarone</span> Medication

Dronedarone, sold under the brand name Multaq, is a class III antiarrhythmic medication developed by Sanofi-Aventis. It was approved by the US Food and Drug Administration (FDA) in July 2009. Besides being indicated in arrhythmias, it was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. The FDA label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in people with moderate to severe congestive heart failure.

<span class="mw-page-title-main">Naltrexone/bupropion</span> Medication for treatment of obesity

Naltrexone/bupropion, sold under the brand name Contrave among others, is a fixed-dose combination medication for the management of chronic obesity in adults in combination with a reduced-calorie diet and increased physical activity. It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone atypical antidepressant. It is taken by mouth. Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some synergistic effects on weight.

<span class="mw-page-title-main">Canagliflozin</span> Chemical compound

Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.

Steven E. Nissen is an American cardiologist, researcher and patient advocate. He was chairman of cardiovascular medicine at the Cleveland Clinic, in Cleveland, Ohio.

Romosozumab, sold under the brand name Evenity, is a medication used to treat osteoporosis. It has been found to decrease the risk of fractures of the spine.

The relationship between antidepressant use and suicide risk is a subject of medical research and has faced varying levels of debate. This problem was thought to be serious enough to warrant intervention by the U.S. Food and Drug Administration to label greater likelihood of suicide as a risk of using antidepressants. Some studies have shown that the use of certain antidepressants correlate with an increased risk of suicide in some patients relative to other antidepressants. However, these conclusions have faced considerable scrutiny and disagreement: A multinational European study indicated that antidepressants decrease risk of suicide at the population level, and other reviews of antidepressant use claim that there is not enough data to indicate antidepressant use increases risk of suicide.

References

  1. ↑ "The heading and the summary must be contained within a box and bolded." 21CFR201.57 Subpart B (a)(4)
  2. 1 2 "Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products — Content and Format" (PDF). Guidance for industry. Even in the context of clinical research, human subjects are often not informed about the risks included in boxed warnings for drugs they are being given. For protocols involving drugs with boxed warnings, 63% of consent forms did not disclose 1 or more boxed warning risks. Warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products—content and format. U.S. Food and Drug Administration . Retrieved February 21, 2010.
  3. ↑ "Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers". National Institute of Mental Health. Archived from the original on March 1, 2010.
  4. ↑ Shah ND, Montori VM, Krumholz HM, Tu K, Alexander GC, Jackevicius CA (November 2010). "Responding to an FDA warning--geographic variation in the use of rosiglitazone". The New England Journal of Medicine. 363 (22): 2081–2084. doi:10.1056/NEJMp1011042. PMID   21083379.
  5. ↑ Cohen A, Rabbani A, Shah N, Alexander GC (April 2010). "Changes in glitazone use among office-based physicians in the U.S., 2003-2009". Diabetes Care. 33 (4): 823–825. doi:10.2337/dc09-1834. PMC   2845035 . PMID   20103549.
  6. ↑ Fornaro M, Anastasia A, Valchera A, Carano A, Orsolini L, Vellante F, et al. (2019). "The FDA "Black Box" Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits?". Frontiers in Psychiatry. 10: 294. doi: 10.3389/fpsyt.2019.00294 . PMC   6510161 . PMID   31130881. On October 2004, the FDA required a so-called black box warning for antidepressant drugs of any class. That warning became effective in January 2005. In 2006, the FDA warning extended to young adults aged up to 25 years, an announcement that followed a slew of media reports about the link between antidepressant drug use and suicide, possibly culminating in an exaggerated alarmist message.
  7. ↑ Ho D (June 2012). "Antidepressants and the FDA's black-box warning: determining a rational public policy in the absence of sufficient evidence". The Virtual Mentor. 14 (6): 483–488. doi:10.1001/virtualmentor.2012.14.6.pfor2-1206. PMID   23351264.
  8. ↑ "Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection". Food and Drug Administration . Archived from the original on August 9, 2007. Retrieved August 15, 2007.
  9. ↑ "COX-2 Selective (includes Bextra, Celebrex, and Vioxx)". U.S. Food and Drug Administration. April 7, 2005. Retrieved January 2, 2024.
  10. ↑ Corbett J (August 2, 2005). "Celebrex to Get 'Black Box' Label On Heart Risks". The Wall Street Journal. Retrieved January 2, 2024.
  11. ↑ Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC (January 2010). "Impact of FDA black box advisory on antipsychotic medication use". Archives of Internal Medicine. 170 (1): 96–103. doi:10.1001/archinternmed.2009.456. PMC   4598075 . PMID   20065205. Archived from the original on July 27, 2011.
  12. ↑ Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. (May 2012). "Risk of natalizumab-associated progressive multifocal leukoencephalopathy". The New England Journal of Medicine. 366 (20): 1870–1880. doi: 10.1056/NEJMoa1107829 . PMID   22591293.
  13. ↑ "TOUCH Program". TOUCH On-Line. Biogen Idec. Retrieved September 8, 2016.
  14. ↑ "Black Box for Warfarin" . Retrieved August 15, 2007.
  15. ↑ "Strongest warning suggested for ADHD drugs". CNN. Associated Press. February 10, 2006. Archived from the original on August 18, 2007. Retrieved August 15, 2007.
  16. ↑ "'Black Box' ADHD Drug Warning Rejected". CBS News . March 22, 2006. Retrieved August 15, 2007.
  17. ↑ Pediatric Advisory Committee documentation available at: "2006 FDA Advisory Committees Meeting Documents by Center". U.S. Food and Drug Administration. February 5, 2007. Retrieved August 15, 2007.
  18. ↑ Drug Safety and Risk Management documentation available at: "CDER 2006 Meeting Documents". U.S. Food and Drug Administration. February 1, 2007. Retrieved August 15, 2007.
  19. ↑ "Glaxo's Avandia to carry heart-attack warning". MarketWatch. November 14, 2007. Retrieved November 14, 2007.
  20. ↑ "FDA orders 'black box' label on some antibiotics". CNN. July 8, 2008. Retrieved July 8, 2008.
  21. ↑ FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". Food and Drug Administration . Archived from the original on October 19, 2010. Retrieved July 1, 2009.
  22. ↑ "FDA Announces Addition of Boxed Warning to METACAM® (meloxicam) Labels". October 27, 2010.
  23. ↑ "Thyrolar (liotrix) dosing, indications, interactions, adverse effects, and more".
  24. ↑ "FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects". July 29, 2013.
  25. ↑ Lan H, Jun-yi Z (2014). 国内外药品说明书和标签管理中有关警示语的比较研究 [Comparison of Related Content of Warnings in Drug Labels and Package Inserts at Home and Abroad](PDF). 中国药房. 33. doi:10.6039/j.issn.1001-0408.2014.33.29 (inactive January 31, 2024).{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  26. ↑ Alshammari TM, Devadasu VR, Rathnam RP (December 2017). "Comparison of the safety information on drug labels in three developed countries: The USA, UK and Canada". Saudi Pharmaceutical Journal. 25 (8): 1103–1107. doi:10.1016/j.jsps.2017.07.006. PMC   6111122 . PMID   30166896.
  27. ↑ "PAXLOVID". Pfizer Medical Information - Canada.
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